Tetrahedron Vol. 41, No. 32, Pp. 6493-6502.1991 Priitcd in Great Britain

0040-4020/91 $3.00+.00 0 1991 Pcrgmnon Press p

Structural Studies on Benxothiazoles. Crystal and Molecular Structure of 5,6-Dimethoxy-Z-(4-

methoxyphenyl)-benzothiazole and Molecular Orbital Calculations on Related Compounds’.

PAUL C YATES2, CAROL J MCCALL AND MALCOLM F G STEVENS

Pharmaceutical Sciences Institute Department of Pharmaceutical Sciences

Aston University Aston Triangle

Birmingham B4 7ET United Kingdom

(Received in UK 8 May 1991)

Key Words: benrothiazole; crystal structure; molecular mechanics; molecular orbital calculations; torsional barrier

Abstract

The benzothiazole derivatrves reported here have structural similanties to the 2-phenylindole

derivatives that are known to bind to oestrogen receptors. We report the synthesis of 5,6-

dimethoxy-2-(4_methmtyphenyl)- benzothiazole together with the determination of its three

dimensional crystal structure. Crystals are monoclinic, space group P2r/c, a=17.142(1),

b=11.165(1), c=7.683(2) A, @=101.34(1)0. 2307 Reflections were refined to R=0.039. The

inter-rmg twist angle is 21°, greater than in 2-(o-hydroxyphenyl)benzothmzole but similar to

that in 2-(4’-bromophenyl)-4,6-dimethoxyindole. Molecular mechanics calculations predict a

torsional barrier to inter-ring twist of 6.3 kcal mol-’ for unsubstituted benzothiazole. Molec-

ular orbital calculations show that while hydrogen bonding can confer stability on substituted

benzothiazoles, a greater number of non-hydrogen bonding groups se substituents can confer

even greater stability.

‘Supplementary data avarIable (atomrc thermal parameters, structure factors). See Notice to Authors. Tetr‘ahedron. 40(2). ;I-(1984).

‘Present address: Department of Chenustry, Umverslty of Keele. Keele. Staffordshue ST5 5BG. Umted Kingdom

6493

6494 P. c. YATES et al.

Hydroxy-substituted 2-phenylindoles have been shown to have high relative binding affimties

for the oestrogen receptor and thus have potential for the treatment of hormone dependent breast

cancer’. A systematic study of a series of Z-phenylindole derivatives has considered bmding affimty

for the oestrogen receptor, mammary tumour inhibiting activity and oestrogemc and anti- oestrogenic

properties’. It is possible that benzothiazole compounds (compound (1) and its derivatives) having

a similar rmg structure wiII show related activity, and in this paper we look at the structures of a

number of these compounds. The crystal structure of a simple benzothiazole compound has been

determined (compound (2))2, but this structure is complicated by the presence of an intramolecular

hydrogen bond.

Compound RI R2 R3 lb

(1) H H H H

(2) H H OH H

(3) OCHa OCHs H OCHs

5,6-dimethoxy-2-(4-methoxyphenyl)-benzothiazole (3) was synthesised vta the Jacobsen method3

from the corresponding trimethoxy thioamide.This benzothiazole is intended to act as the precursor

to a series of substituted benaothiazoles, and we report its three dimensional crystal structure as

determmed by X-ray diffraction.

CRYSTAL AND MOLECULAR STRUCTURE OF (3)

The crystal had dimensions 0.35 x 0.35 x 1.25 mm. The data were collected on an Enraf-

Nonms CAD4 diffractometer with monochromated MO-K, radiatton, X = 0.71069 A, CtsHisNOaS,

ML301.4, monoclimc, a=17.142(1), b=11.165(1), c=7.683(2) A, ,0=101.34(l)“, V=1441.7(9) A3,

Z=4. D,=1.35(2) g cmm3, D,=l.39 g cmW3, F(000)=632, p(Mo- K,)=1.88 cm-i, space group P2i/c.

The 3134 intensity data were collected by the w-20 scan technique, and of these 2307 reflections were

Structural studies on benzothiazoles 6495

deemed observed with IF,/ >2.50. Using SHELX-76’, an E-map was produced in which all but four of

the non-hydrogen atoms were located. These remaining atoms were located in a subsequent Fourier

map. Hydrogen atoms were included in calculated positions and all atoms refined isotroprcahy.

Further refinement with amsotropic non-hydrogen atoms reduced the unweighted discrepancy index

to R = 0.039 (R, = 0.046). In the latter stages of refinement, reflections were weighted according

to w = K/[o’(F)+O.OO~F~]. Full-matrix refinement was used, with the quantity ~w(F,-F,)~ being

minimised. Refinement was terminated with the maximum value of shift/e.s.d. being 0.031. Finally

a difference electron density map was calculated which showed no feature greater than 0.28 e Am3.

Calculations were performed on the VAX 8650 Cluster at Aston Umversity. Observed and calculated

structure factors, and atom thermal parameters are given in a Supplementary Publication. Scattermg

factors were taken from reference 5.

Figure 1: Crystal structure of 5,6-dimethoxy-2-(4- methoxyphenyl)-benzothiazole (2) as determined by X- ray diffraction

J

Atomrc coordmates are grven in Table 1, and a molecule of (3) is shown m Figure 1 which

was produced with the ORTEP program’j on the Amdahl 5890-300 computer at the Manchester

6496 P. C. YATES et al.

Table 1. Final atomic coordinates (~10~) for (3) with estimated standard deviations in parentheses.

Atom x/a C(1) -2210(2)

O(2) -1921(l)

C(3) -1124(l)

C(4) -0840(l)

C(5) -0050(l)

C(6) 0489(l)

C(7) 0193(l)

C(8) -0601(l)

C(9) 1326(l)

NC101 1593(l)

cc111 2410(l)

SC121 2053(O)

cc131 2772(l)

cc141 3592(l)

cc151 4038(l)

C(16) 3669(l)

cc171 2870(l)

O(18) 4175(l)

y/b 3059(3) 3803(l)

3773(2)

4664(2) 4707(2)

3861(2)

2975(2)

2925(2)

3918(2)

4455(l)

4326(2) 3225(O)

3685(2)

3466(2)

3877(2)

4487(2)

4718(2)

4790(2)

Z/C

-1640(4)

-0154(2) 0531(3)

1774(3)

2549(2)

2115(2)

0891(3)

0098(S)

2974(2)

4482(2)

4980(2) 2000(l)

3786(3)

4132(3)

5712(3)

6963(3)

6597(3)

8514(2)

Atom x/a C(N) 3817(l)

O(20) 4840(l)

cc211 5246(l)

H(40) -1245(l)

H(50) 0164(l)

H(70) 0597(l)

H(80) -0818(l)

H(lOl) -2827(2)

H(102) -2146(2)

H(103) -1854(2)

H(l40) 3865(l)

H(170) 2596(l)

H(191) 4317(l)

H(192) 3407(l)

H(193) 3518(l)

H(211) 5878(l)

H(212) 5131(l)

H(213) 5033(l)

y/b Z/C 5172(3) 9944(3)

3733(2) 6228(2)

3157(3) 5010(4)

5323(2) 2119(3)

5401(2) 3502(2)

2314(2) 0545(3)

2227(2) -0846(3)

3237(3) -2206(4)

2141(3) -1194(4)

3208(3) -2633(4)

2985(2) 3189(3)

5198(2) 7541(3) 5227(3) 11043(3)

4495(3) 10218(3)

6028(3) 9766(3)

3155(3) 5539(4)

3601(3) 3736(4)

2245(3) 4852(4)

Computmg Centre Geometric parameters are given in Table 2, showing that the C-O distances

are much as expected at around 1.424 A. C-C bond lengths within the isolated phenyl nng range

from 1.368 to 1.404 A with an average of 1.388 A, while in the benzothiazole moiety they average

1.396 A with a range from 1.368 to 1.423 A. The C(6)-C(9) ’ t m er-ring bond length of 1.457(3) 8, IS

rather shorter than the 1.487 A expected for biphenyl compounds ‘I and that observed m (2). The

N(lO)-C( 11) and S(12)-C(13) lengths of 1.385 and 1.732 A respectively are both shorter than the

correspouding value found m (2), but other N-C and S-C bond lengths show a closer agreement.

The bond angles are largely unexceptional, but the angles around the ether oxygens are con-

siderably greater than tetrahedral, being approximately 117’. In the su( membered ring of the

benzothiazole and the 2-phenyl ring, angles range from 115.7 to 124.7’ and from 109.4 to 129.0”

respectively, with the corresponding averages bemg close to the ideal at 120.3 and 119.4O. The angle

made at the sulphur atom is, as expected, lower at 89.2”. Table 2 shows that the Inter-rmg twist angle

about the C(6)-C(9) bond is 21”, suggesting a considerable loss of conjugation. This is comparable

to the value of 29” 111 2-(4’-bromophenyl)-4,6-dimethoxyindole*. The torsion angles about the C-O

bonds also differ from their ideal values by up to 13”; this is not too surprismg in view of the lower

barrier to rotation about these single bonds. The molecule contains no potential hydrogen bonding

groups. but there are a number of interatomic contacts at distances less than the sum of the van

Table 2. Geometric parameters in (3). Length.9 in A and angles in degreea.

C(l)-O(2) 0(2)-c(3)

C(3)-C(4)

c(3)-c(8)

C(4)-C(5)

C(5)+(6)

c(6)-c(7)

C(~)+(Q) c(7)-c(8) C(Q)-N(10)

C(Q)-S(12)

1.420(3)

1.364(2)

1.398(3)

1.388(3)

1.368(3)

1.407(3)

1.391(2)

1.457(3) 1.379(3)

1.305(2)

1.754(2)

N(lO)-C(U)

C(ll)-C(13)

C(li)-C(17)

S(12)-C(13)

C(13)-C(14)

C(14)-C(15)

C(15)-C(16)

C(lS)-O(20) C(l6)-C(l7)

C(16)-O(18)

0(18)-C(19)

0(20)-C(21) 1.426(3)

C(l)-0(2)-C(3) 117.5(2)

O(2)-C(3)-C(4) 115.7(2)

O(2)-C(3)%(8) 124.7(2)

C(3)-C(4)-C(5) 120.2(2)

C(4)-C(S)-C(6) 120.9(2)

C(5)-C(S)-C(7) 117.9(2)

C(5)-C(S)-C(9) 119.8(2)

C(7)-C(6)-C(S) 122.2(2)

C(6)-C(7)-C(8) 121.7(2)

C(3)-C(8)-C(7) 119.6(2)

C(6)-C(Q)-N(10) 124.4(2)

C(6)-C(Q)-S(12) 120.4(l)

N(lO)-C(S)-S(12) 115.2(l)

C(Q)-N(lO)-C(11) 110.9(2)

N(lO)-C(U)-C(17) 125.0(2)

C(4)-C(3)-C(8) 119.6(2)

C(5)-C(6)-C(Q)-N(10) 21.3

C(S)-C(S)-C(S)-S(12) -159.4

O(18) . . . O(18) Cl-x,1-y,l-z]

O(18) . . . C(19) Cl-x,1-y.l-21

O(2) . . . S(12) Cl-x,1-y,l-21

1.385(2)

1.401(3)

1.404(3)

1.732(2)

1.400(3)

1.380(3)

1.423(3)

1.363(2) 1.368(3)

1.372(2)

1.425(3)

N(lO)-C(U)-C(13)

c(13)-c(ll)-c(17)

C(Q)-S(12)-C(13)

C(ll)-C(13)-S(12) C(ll)-C(l3)-C(14)

S(12)-C(13)-C(14)

C(13)-C(14)-C(l5)

C(14)-C(15)-C(16)

C(14)-C(15)-O(20)

C(16)-C(lS)-O(20)

C(15)-C(l6)-C(17)

C(15)-C(16)-O(18)

C(ll)-C(17)-C(16)

c(16)-0(18)-c(19)

C(15)-0(20)-C(21)

115.2(2)

119.7(2)

89.2(l)

109.4(l)

121.5(2)

129.0(2)

118.1(2)

120.7(2)

124.7(2)

114.6(2)

120.8(2)

114.6(2)

119.2(2)

116.7(2)

117.2(2)

W)-C(~)-C(S)-N(~O) -157.3

C(~)-C(~)-C(Q)-S(~~) 22.0

3.301

3.414

3.598

6497

S(12) . . . S(12) [x.0.5-y,o.5+21 4.169

N(10) . . . S(12) [x,0.5-y,o.5+21 3.566

S(12) . . . C(17) [x,0.5-y,O.5+zl 3.609

C(11) . . . S(12) [x,0.5-y.O.5+zl 3.357

S(12) . . . C(13) [x,0.5-y.O.5+zl 3.656

6498 P. C. YATES et al.

der Waals’ radii, in particular involving the sulphur atom. These indicate a fairly tightly packed

structure. A stereo view of the molecule is shown in Figure 2.

Figure 2: Stereo view of 5,6- dimethaxy-2-(4-methoxyphenyl)-benzothiazole (3)

MOLECULAR MECHANICS AND MOLECULAR ORBITAL CALCULATIONS

Our crystallographic results show a significant twist between the two ring systems in compound

(3). This compares with compound (2) where the rings are planar, but a8 noted earlier this may

well be due to the presence of a strong intramolecular hydrogen bond. This feature in (2) makes

comparison difficult, so we have investigated this aspect of the benzothiazole structures further

through the use of molecular mechanics and molecular orbital calculations.

A model of (1) was built by modifying the crystal structure of (3) with the Chem-X program’,

and the dihedral driver option of the MM2 molecular mechanics program” was used to drive the

inter-ring torsion angle through 360”. The resulting plot of steric energy against torsion angle is

Structural studies on benzothiazoles 6499

I -200 -150

C($i(6,--5diS)-N&O) To5Psion LY$ 150 *O”

Figure 3: Graph of Steric Energy versus inter-ring Torsion Angle for Compound (1).

shown in Figure 3. This predicts a planar structure for the unsubstituted benzothiasole molecule

(l), leading to maximum conjugation in the absence of hydrogen bonding or steric interaction effects.

The calculations also predict a torsional barrier to rotation of 6.3 kcal mol-’ in this molecule.

Molecular orbital calculations were then performed on the planar conformation of (1) together

with the crystal structure conformations of (2) and (3). The STO-3G basis set was used with the

GAUSSIAN86 program l1 . The size of these molecules precludes the use of more elaborate basis sets.

The resulting partial atomic charges, dipole moments and Restricted Hartree Fock energies are given

in Table 3.

The charges on the nitrogen and sulphur atoms are considerably larger than those on the carbons

in all three molecules, and are approximately equal in magnitude in (1) and (3). However in (2) the

presence of hydrogen bonding results in a larger negative charge on the nitrogen atom. The smallest

charges on carbon atoms result for those in the inter-ring bond, and negative charges result for the

bridgehead carbon adjacent to the nitrogen atom and for those which have non-hydrogen substituents

attached. The trend in dipole moments seen is consistent with the number of substrtuents in each

6500 P. c. YATES et al.

Table 3. Atomic charges from molecular orbital calculations.

AtOm (1) (2) (3) C(3) -0.08 -0.08 0.14 C(4) -0.08 -0.15 -0.08 C(5) -0.05 0.19 -0.04 C(8) -0.01 -0.08 -0.02 C(7) -0.08 -0.08 -0.05 C(8) -0.08 -0.08 -0.10 C(9) 0.01 0.03 0.01 NC101 -0.27 -0.32 -0.27 CC111 0.08 0.07 0.08 SC121 0.24 0.24 0.23 C(13) -0.11 -0.10 -0.11 C(14) -0.07 -0.09 -0.10 Cf15) -0.08 -0.09 0.13 C(l8) -0.07 -0.08 0.11 C(17) -0.08 -0.07 -0.09

Dipole moment(D) 1.29 2.48 2.98 RIiF Energy (AU) -938.41 -1012.09 -1275.88

molecule. Hydrogen bonding clearly provides considerable electronic stability for (2) compared to

(l), but it is noteworthy that the more highly substituted (3) has‘s lower RHF energy than either.

CONCLUSIONS

The preferred conformation df benrothiasole compounds is very dependent on the number and

nature of the substituents present. A planar structure is preferred for unsubstituted compounds and

for those which can form hydrogen bonds in such a conformation. However, greater electronic stabil-

ity may be obtained by increasing the number of substituents, even if they do not exhibit hydrogen

bonding properties.

Structural studies on benmthiazoles

EXPERIMENTAL PROCEDURE

6501

U v. spectra were recorded on a Pye Unicam SPSOOO Ultraviolet Recording Spectrophotometer,

i.r. spectra on a Perkin-Elmer 1310 Infrared Spectrophotometer and 300 MHz n.m.r. spectra on a

Bruker AC300 NMR Spectrometer. The t.1.c. systems employed Kieselgel 60F254 (0.25 mm) as the

absorbant. Meltmg points are uncorrected.

3,4,4’-Tnmethoxythiobenzanilide: 3,4,4’- trimethoxybenzanilide was obtained by stirring 4

aminoveratrole with an equimolar ratio of 4- methoxybenzoyl chloride in pyridine (1 h) washing the

product with water and recrystallising from methanol. A mixture of 3,4,4’-trimethoxybenzanihde

(4.00 g) and Lawesson’s reagent (2.82g) was refluxed (1 h) in chlorobenzene. After cooling the solid

produced was filtered off and recrystallised from methanol to yield yellow crystals, m.p. 139-140°C

(Found : C, 63.2; H, 5.5; N, 4.9%; M+, 303. CrsHtrNOsS requires C, 63.4; H, 5.6; N, 4.6%); v,,

(nujol) 3160 (NH), 1590 cm -‘; C(CDClz) 8.96 (lH,s), 7.83 (2H,d), 7.47 (lH,s), 7.08 (lH,d), 6.86

(3H,t), 3.86 (3H,s), 3.85 (3H,s), 3.83 (3H,s) ppm; X,, (EtOH) 219. 263, 337 nm; Rf (CHaCI) 0.24.

5,6-Dimethoxy-2-(4-methoxyphenyl)benzothiazole (3) - A suspension of finely divided 3,4,4’-

tnmethoxythiobenzanilide (1.00 g) in 10% NaOHt,, ( 21 ml) was added slowly to a stirred solutiou

of potassium ferricyanide (4.34 g) in water (15 ml), mamtained at 80-85°C. The mixture was heated

for a further hour then cooled to room temperature and stirred overnight. The solid produced was

filtered, washed and recrystailised from methanol to grve cream needle crystals, m.p. 159-160 “C

(Found: C, 63.7; H, 5.0; N, 4.7%; M+, 301. CrsHrsNOsS requires C, 63.8; H, 5.0; N, 4.7%); v,,,,,

(nuJo1) 1590, 1280, 1240, 1210, 1150, 830 cm-l; C(CDCla) 7.93 (2H,d), 7.49 (lH,s), 7.25 (lH,s), 6.90

(2H,d), 3.94 (3H,s), 3.93 (3H,s), 3.84 (3H,s) ppm; X,, (EtOH) 239, 354 nm; RI (CHCIs) 0.20.

ACKNOWLEDGEMENTS

We would like to thank Dr. P.R. Lowe for assistance with the crystallographic mvestigations.

6502 P. c. YATES et al.

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